Poor outcomes among critically ill HIV-positive patients at hospital discharge and post-discharge in Guinea, Conakry: A retrospective cohort study

Introduction Optimal management of critically ill HIV-positive patients during hospitalization and after discharge is not fully understood. This study describes patient characteristics and outcomes of critically ill HIV-positive patients hospitalized in Conakry, Guinea between August 2017 and April 2018 at discharge and 6 months post-discharge. Methods We carried out a retrospective observational cohort study using routine clinical data. Analytic statistics were used to describe characteristics and outcomes. Results 401 patients were hospitalized during the study period, 230 (57%) were female, median age was 36 (IQR: 28–45). At admission, 229 patients (57%) were on ART, median CD4 was 64 cells/mm3, 166 (41%) had a VL >1000 copies/ml, and 97 (24%) had interrupted treatment. 143 (36%) patients died during hospitalisation. Tuberculosis was the major cause of death for 102 (71%) patients. Of 194 patients that were followed after hospitalization a further 57 (29%) were lost-to-follow-up (LTFU) and 35 (18%) died, 31 (89%) of which had a TB diagnosis. Of all patients who survived a first hospitalisation, 194 (46%) were re-hospitalised at least once more. Amongst those LTFU, 34 (59%) occurred immediately after hospital discharge. Conclusion Outcomes for critically ill HIV-positive patients in our cohort were poor. We estimate that 1-in-3 patients remained alive and in care 6 months after their hospital admission. This study shows the burden of disease on a contemporary cohort of patients with advanced HIV in a low prevalence, resource limited setting and identifies multiple challenges in their care both during hospitalisation as well as during and after re-transitioning to ambulatory care.


Introduction
While roll out of Anti-Retroviral Treatment (ART) in Sub Saharan Africa has decreased, the burden of HIV [1] and mortality due to HIV remains elevated in Western and Central Africa (WCA) [2]. Advanced HIV disease remains a major issue, both due to late presentation of new patients as well as ART-experienced patients who drop out of treatment [3]. Availability and quality of HIV care differs between the low prevalence countries of Western and Central Africa (WCA) and Southern and Eastern Africa (SEA) [4]. Despite only contributing 17% of worldwide HIV cases, WCA accounts for 31% of HIV mortality globally, as well as 21% of new infections [4]. In Guinea, about 120,000 people live with HIV, the prevalence within the adult population (15-49 years) is low (1.5%), [5] and around 35% of HIV positive adults are estimated to be on ART [5,6]. Access to diagnostic testing for opportunistic infection (OIs), HIV viral load or CD4 count remain limited and HIV programs encounter intermittent drug supply ruptures.
Recent improvements in the management of advanced HIV-patients include the provision of tailored treatment interventions and the recommendation to consider switch from 1 st to 2 nd line ART on only 1 elevated VL in severely ill patients with a fitting history [7,8], although it is currently unclear whether these new recommendations are adhered to in practice. Acquired drug resistance in patients who fail 1 st line treatment is of growing concern [8], with a Guinean study from 2014 among treatment experienced patients with virologic failure reporting at least one drug resistance mutation (DRM) in 68% of cases [9]. Recent WHO data for neighbouring Senegal is similar, where 7% of all patients on ART and 63% of patients with a viral load >1000copies/ml showed at least one DRM [10]. Also, failing patients in Sub-Saharan Africa still present with low CD4 counts, making effective treatment and rapid immune reconstitution a priority [7,11]. Primary resistance is rare, with one small Guinean study estimating the prevalence of DRM in treatment naïve patients as low as 6.45% [12,13].
MSF has supported HIV care in Guinea since 2003. Since 2016, MSF supports the unit of care, training and research (USFR), a tertiary level referral hospital run by the ministry of health (MOH). USFR is dedicated to the care of HIV patients in need of hospitalisation. Until now however, there is virtually no data on the long term outcomes of patients with advanced HIV in the WCA region. This study aims to address this gap by describing profiles and outcomes at discharge and post-discharge of critically ill HIV-positive patients who were hospitalised at USFR, Conakry, Guinea, between August 2017 and April 2018.

Study design
We carried out a retrospective observational cohort study on routine data of all patients with HIV infection admitted to USFR Donka between August 2017 and April 2018. Post-discharge Long-term outcomes were presented from date of discharge from hospital as the start date. Any patient who was lost at the day of exit was assigned one day of follow up time. Outcomes during follow up were classified as alive (including patients referred to other facilities at study censor), dead or LTFU which was defined as missing the last scheduled clinic appointment by a period of 90 days, or 90 days since hospitalisation if the patient was lost immediately after hospitalisation. Tiernet would automatically classify patients as LTFU if their appointment was missed, and project staff would actively follow up patients who were classified as LTFU to encourage them to come back to care, or to confirm their outcome classification. We also included the outcome attrition, which combined LTFU and dead. Chi squared tests and fisher's exact tests were used as appropriate to test for differences between alive, dead and LTFU by categorical baseline characteristics. Chi squared tests were carried out with and without missing data in order to understand if the missing data might affect the analyses. Comparisons of medians by the three outcomes were calculated using k-sample comparison of medians. A two-sided alpha <0.025 threshold was considered as statistically significant for all analyses. All analyses were conducted with STATA version 15, and data cleaning was conducted in Microsoft Excel 2016.
Ethical committee approval. The study was approved by the national ethics committee for health research (CNERS) reference 113/CNERS/2018 in Guinea who waived the requirement for informed consent. Also, the study fulfilled the exemption criteria set by the doctors without borders Ethics Review Board for a posteriori analyses of routinely collected clinical data and thus did not require MSF ERB review. It was conducted with permission from the Medical Director, Operational Centre Brussels, Belgium. As an a posteriori analyses of routinely collected clinical data, no individual consent was sought for this study.

Patient outcomes
The outcomes of all patients at the end of the 6 month follow up period, are shown in Table 2: 102 (53%) remained active, with 5 among them being censored as they were transferred out of the cohort, 57 (29%) were LTFU and 35 (18%) died. Of those that were lost to follow up, 34 (59%) were lost immediately after an IPD episode, and never returned for their follow-up OPD appointment which were routinely scheduled 3-5 days after hospitalisation. Overall, 67 (35%) were re-hospitalized once or twice and 22 (11%) were re-hospitalized at least 3 times. Of those re-hospitalized 26 (47%) died in-hospital. The median time to rehospitalization at USFR was 55 days (IQR:32-99).
Patients with a documented treatment interruption had comparable outcomes during hospitalization to patients without a documented treatment interruption (33 (34%) vs 81 (39%) p = 0.425) mortality, respectively. However, during follow up those with a treatment interruption had higher level of attrition (27 (63%) vs 45 (45%) p = 0.033) than patients with no treatment interruption. Patients on second line (44%) or who had been on first line for more than 6 months (57%) were more likely to have a recorded treatment interruption than those who had been on treatment for less than 6 months (37%) (p<0.001). Outcomes for patients at hospital discharge and during follow up were similar for ARV naïve and experienced patients (p = 0.726, p = 0.440).

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Outcomes of HIV positive patients in Guinea, Conakry Mortality rates during hospitalization and attrition post-hospitalization stratified by viral load status were similar. Patients who had had only undetectable viral loads recorded either during, before or after hospitalization, had better outcomes overall. As shown in Tables 1 and 2, patients who had no VL recorded or who had any number of VL recorded above undetectable (taken to be above 40 copies/ml) had poor outcomes, regardless of ARV regimen or switch to second line.

ARV initiation and treatment failure
At hospital admission, 161 (40%) patients reported to be treatment naïve, 56 (35%) of which were initiated on 1 st line ART during hospitalization. 171 (43%) of the 401 hospitalized patients and 96 (49%) of the 194 patients followed up post-discharge had one viral load above 1000 copies/ml recorded at admission, 16 (4%) and 30 (15%) patients had two VL>1000 recorded during or before hospitalization, respectively. On the basis of two elevated viral loads among patients with 1 st line ART exposure>6 months, only 1 (9%) out of 11 patients eligible for switch to 2 nd line ART was switched during At the end of the study period, 3 out of 6 (50%) among those that were switched and 15 out of 23 (70%) among those that were not, were no longer in care.
Of the 11 patients on second line treatment, none were switched to third line, although 3 (27%) did have two VL recorded above 1000 copies/ml.

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Outcomes of HIV positive patients in Guinea, Conakry Tables 3 and 4 show major opportunistic infections (OIs) and associated conditions at exit for hospitalized patients and those followed up post-discharge. 84 (21%) patients presented with a haemoglobin level of below 7g/dl and 137 (34%) patients presented with severe malnutrition. Tuberculosis (TB) was the most frequent clinical diagnosis at exit with 295 (74%) diagnoses as well as the leading cause of mortality with 101 deaths (70%). 123 (31%) patients showed signs of disseminated TB, 63 (16%) were diagnosed with TB meningitis. 52 (13%) and 36 (9%) TB cases were diagnosed without biological confirmation and already on treatment at admission, respectively. Of the 295 patients with a primary diagnosis of TB, 68 (23%) had no other diagnosis. Additional diagnosis amongst patients with TB were: Toxoplasmosis (30%), diarrhoea (19%), oesophageal candidiasis (19%), PCP (16%) and Cryptococcal meningitis (CM) (6%). Out of 55 patients that were hospitalized at USFR for a 2 nd time, 20 (36%) had a different diagnosis. One case who initially was recorded as a case of chronic diarrhoea was diagnosed with CM upon 2 nd hospitalization, while two TB cases were diagnosed with Toxoplasmosis during their 2 nd hospitalization. Tables 3 and 4 show that rates of death and attrition during and after hospitalization are similar for all OIs. One exception is that patients with signs of severe acute kidney injury had worse outcomes than patients with other conditions with 23 (57%) p = 0.002 dying during hospitalization, and 7 (50%) p = 0.650 being LTFU or dead during the 6 months of follow up.

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Outcomes of HIV positive patients in Guinea, Conakry

Discussion
To our knowledge, this is the first study reporting post-hospitalisation survival data in HIV patients in a West African context. Survival rates in our cohort were extremely low. Whilst mortality rates for patients with advanced HIV disease are generally poor across the published literature, outcomes for this cohort are amongst the worst and are not substantially different to outcomes of the pre-cART era globally [15]. Contemporary studies from Kinshasa [16], Ethiopia [17], Ghana [18] and Senegal [19] report similarly poor in-hospital mortality of HIV positive patients with 30%, 29%, 40% and 44% respectively. A study published in 2019 in Zambia showed better outcomes with 5.4% and 22% mortality at discharge and 3 months post-discharge respectively, though this study excluded critically ill patients [20].
In our cohort, 40% and 35% of patients presenting with advanced disease were ART naïve and had been on ART for more than six months, respectively. Awareness of serostatus among HIV positive men and overall ART coverage in Guinea are at 37% and 35%, respectively [5,21] indicating that the global shift in the HIV epidemic from ART naïve towards 1 st line experienced patients has not happened to the same extent in Guinea [10]. Although the true number of treatment experienced patients might be underestimated due to patients underreporting

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Outcomes of HIV positive patients in Guinea, Conakry previous exposure to ARV due to shame and stigma, this finding has important implications. For one, continued efforts to improve HIV screening and ART coverage can go a long way to prevent advanced HIV in Guinea. Second, NNRTI based 1 st line regimens seem to continue to be a viable option, especially given the low rates of primary resistance in this setting [12].

Screening and management of co-morbidities
More than two thirds (73%) of patients were treated for TB. 67% of patients had symptoms for at least 2 weeks, indicating late presentation and or missed chances for earlier detection at OPD level. Almost 80% of patients with a TB diagnosis presented additional co-morbidities. Most additional diagnoses were made based on clinical suspicion which might have led to over-treatment. While potentially resulting in treatment toxicity, empirical treatment is advisable in a context of imperfect diagnostic tools and conditions associated with high mortality. Provision of comprehensive screening and treatment packages in compliance with recent WHO recommendations should be further encouraged [3,7]. Of note, mortality and attrition were particularly high for patients with severe kidney injury. In our cohort however, end-organ failure must be regarded as a proxy of underlying sepsis rather than a standalone condition.

Screening for treatment failure
In this study we applied two different definitions for ART failure and eligibility for switch from 1 st to 2 nd line of ART. Following the definition that was in place during most of the study time period, requiring 2 VL above 1000, only 11 patients would have been eligible. Only two (18%) of those eligible under this definition were switched. This means that out of 125 critically ill patients who were clinically failing while on 1 st line ART for more than 6 months only 9% would have qualified for switch to 2 nd line therapy and as few as 2% were changed. Using an approach where severely sick patients with one raised VL would be considered as ART failures in need of a switch of ART regimen, only 37 out of 125 (30%) patients would have met eligibility criteria for a switch to 2 nd line ART.
It is well known that delayed switch is common and increases mortality among patients with advanced disease [22]. Reasons for delayed switch include concern for side effects and pill burden, complicated protocols as well as organisational challenges such as poor access to laboratory monitoring [23]. Our data suggests that at this moment, switch from 1 st to 2 nd line ARVs in severely ill patients in low resource settings is excessively difficult and rarely done in practice. The study was conducted in a setting with relatively good access to laboratory monitoring so this alone was not considered a principle hindrance, but that more complex barriers to implementation existed that could be elucidated with further research. With increasing rates of ART experienced patients among critically ill HIV-patients and high rates of acquired drug resistance among them [8,16,24], delayed switch will continue to be an important contributor to mortality. Recent changes in WHO guidelines for ART switch in critically ill HIVpositive patients based on just one VL or on clinical grounds alone are an important first step to address this issue [7,8].

Improvements in psychosocial care
In our study, attrition was similar for all patient groups, regardless of switch to second line or of the type and treatment of OIs. Furthermore, 59% of patients who were lost to follow up disappeared immediately post-discharge without any further contact with OPD, nullifying any potential effect that prompt and urgent care as well as timely change to 2 nd line ART might have had. These results indicate that the prompt and effective treatment provided in a specialised car unit was not sufficient for improving treatment outcomes, and there may be other factors at play. The difficulties experienced by hospitalised in-patients in West and Central Africa have been described in a qualitative study from Kinshasa which showed that patients experienced serious mental and social issues [25]. Patients often felt highly stigmatised and hopeless about their situation and many felt unable to disclose their status or ask for help and support from their families. Furthermore, patients with HIV in Guinea Conakry do not always know where their next meal will be coming from after discharged. We therefore urge caution in transferring the results from the study by Shroufi et al. to our setting without further consideration. In this study, the authors estimate that switching from 1 st to 2 nd line treatment on the basis of 1 VL would in itself result in more than 10.000 prevented deaths per year in South Africa [24]. We agree that rapid switch to 2 nd line is paramount for the survival of patients who fail 1 st line ART. However, we hypothesize that measures such as suggested by Shroufi et al. can only draw on their full potential when combined with intensified patient support to facilitate transition to ambulatory care. In their 2017 guideline, WHO recommends psychosocial support after ART initiation in patients with advanced HIV, in order to support patients deal with the difficulties they experience [7]. Evidence of the impact of comprehensive, tailored psychosocial and economic programmes such as support groups, individual or group counselling, cash transfers, and interventions that reduce transport difficulties such as integration, task-shifting or decentralisation have been well described [26][27][28][29][30][31][32] For example data from 2015 reported a 28% reduction in mortality when a medical intervention was combined with home visits in advanced HIV patients starting ART [33].

Limitations
The major limitation to this study is that as a retrospective analysis of routine data, there were challenges with data quality. 64 (25%) of patients who left hospital alive were not followed upeither due to being referred to another hospital (12-5%) or due to data entry errors in their ID code (9-3%), or due to being from a different cohort before admission, with a different ID numbering system 43 (17%). Multivariate analyses of both hospital and follow-up outcomes did not reveal useful information beyond known associations of advanced disease with mortality and were therefore not included. Information on clinical diagnosis used for this study underestimates the true number of diagnoses per patient as the database only recorded two comorbidities. Other non-HIV related diseases may be under notified as OIs were normally prioritized as diagnosis. For some variables (e.g. HIV-VL, CD4), the proportion of missing data was high, especially in patients who died rapidly after admission. Finally, the actual outcome of those LTFU remains uncertain due to the lack of full follow up, as the follow up system only allowed active follow up following a missed, scheduled outpatient appointment, and not always following discharge from hospital as the outpatient monitoring system was separated to the inpatient system. Improvements to the follow up system were made after this study was conducted. Prior research on the issue reports mortality rates among patients LTFU between 12% and 87% [24,[33][34][35]. Given the precarious health of patients at discharge as well as high barriers to treatment in our setting, we must assume a high mortality rate among patients LTFU.

Conclusions
Outcomes for critically ill HIV-positive patients hospitalized in Guinea, Conakry were poor during hospitalization and follow-up. We estimate 1-in-3 patients to be alive and in care 6 months post-discharge. This study highlights the severe nature of advanced HIV in a resource limited, low prevalence context and identifies attrition during transition from hospital to outpatient services as an important pitfall in patients care continuum.